Proteoglycan 4 is Increased in Human Calcified Aortic Valves and Enhances Valvular Interstitial Cell Calcification.

Gonzalo Artiach,Oscar Plunde,Anders Franco-Cereceda,Ljubica Matic,Till Seime,Magnus Bäck,Andres Laguna-Fernandez,Miguel Carracedo

doi:10.3390/cells9030684

Gonzalo Artiach, Oscar Plunde + Show 6 more

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https://doi.org/10.3390/cells9030684

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Journal: Cells	Publication Date: Mar 11, 2020
Citations: 19	License type: CC BY 4.0

Affiliation: Karolinska Institutet, Karolinska University Hospital

Abstract

Aortic valve stenosis (AVS), a consequence of increased fibrosis and calcification of the aortic valve leaflets, causes progressive narrowing of the aortic valve. Proteoglycans, structural components of the aortic valve, accumulate in regions with fibrosis and moderate calcification. Particularly, proteoglycan 4 (PRG4) has been identified in fibrotic parts of aortic valves. However, the role of PRG4 in the context of AVS and aortic valve calcification has not yet been determined. Here, transcriptomics, histology, and immunohistochemistry were performed in human aortic valves from patients undergoing aortic valve replacement. Human valve interstitial cells (VICs) were used for calcification experiments and RNA expression analysis. PRG4 was significantly upregulated in thickened and calcified regions of aortic valves compared with healthy regions. In addition, mRNA levels of PRG4 positively associated with mRNA for proteins involved in cardiovascular calcification. Treatment of VICs with recombinant human PRG4 enhanced phosphate-induced calcification and increased the mRNA expression of bone morphogenetic protein 2 and the runt-related transcription factor 2. In summary, PRG4 was upregulated in the development of AVS and promoted VIC osteogenic differentiation and calcification. These results suggest that an altered valve leaflet proteoglycan composition may play a role in the progression of AVS.

Highlights

Inflammation, thickening, and calcification of the aortic valve is known as aortic valve sclerosis.When aortic valve calcification causes left ventricular outflow obstruction, it is referred to as aortic valve stenosis (AVS)
We show for the first time an increased expression of proteoglycan 4 (PRG4) mRNA in the thickened calcified of for human aortic from 64expression patients and its association with
MRNA in the genes involvedcalcified in cardiovascular calcificationvalves and inflammation in early of disease

Summary

Introduction

Inflammation, thickening, and calcification of the aortic valve is known as aortic valve sclerosis. When aortic valve calcification causes left ventricular outflow obstruction, it is referred to as aortic valve stenosis (AVS). AVS is a common disease, with a prevalence of 2–7% in populations above 65 years old [1]. The aortic valve is composed of three distinct extracellular matrix (ECM) layers. Closer to the aortic side is the fibrosa, formed by valvular interstitial cells (VICs) and collagen. Primary antibodies diluted in Da Vinci Green solution were applied and incubated at room temperature for 1 h. Warp Red (for PRG4) and Vina Green (for BMP2 and RUNX2). The following primary antibody was used in the study: anti-PRG4 (HPA028523; Sigma, St. Louis, MO, USA)

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